bims-hummad Biomed News
on Humanised mouse models of autoimmune disorders
Issue of 2024–10–27
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer.
  2. Long-Term Human Immune Reconstitution, T-Cell Development, and Immune Reactivity in Mice Lacking the Murine Major Histocompatibility Complex: Validation with Cellular and Gene Expression Profiles.
  1. Nat Biomed Eng. 2024 Oct 21.
    Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer.
    Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu.
      Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of 'universal' immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β2-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
    DOI:  https://doi.org/10.1038/s41551-024-01264-w
  2. Cells. 2024 Oct 12. pii: 1686. [Epub ahead of print]13(20):
    Long-Term Human Immune Reconstitution, T-Cell Development, and Immune Reactivity in Mice Lacking the Murine Major Histocompatibility Complex: Validation with Cellular and Gene Expression Profiles.
    Milita Darguzyte, Philipp Antczak, Daniel Bachurski, Patrick Hoelker, Nima Abedpour, Rahil Gholamipoorfard, Hans A Schlößer, Kerstin Wennhold, Martin Thelen, Maria A Garcia-Marquez, Johannes Koenig, Andreas Schneider, Tobias Braun, Frank Klawonn, Michael Damrat, Masudur Rahman, Jan-Malte Kleid, Sebastian J Theobald, Eugen Bauer, Constantin von Kaisenberg, Steven R Talbot, Leonard D Shultz, Brian Soper, Renata Stripecke.
       BACKGROUND: Humanized mice transplanted with CD34+ hematopoietic cells (HPCs) are broadly used to study human immune responses and infections in vivo and for testing therapies pre-clinically. However, until now, it was not clear whether interactions between the mouse major histocompatibility complexes (MHCs) and/or the human leukocyte antigens (HLAs) were necessary for human T-cell development and immune reactivity.
    METHODS: We evaluated the long-term (20-week) human hematopoiesis and human T-cell development in NOD Scid Gamma (NSG) mice lacking the expression of MHC class I and II (NSG-DKO). Triplicate experiments were performed with HPCs obtained from three donors, and humanization was confirmed in the reference strain NOD Rag Gamma (NRG). Further, we tested whether humanized NSG-DKO mice would respond to a lentiviral vector (LV) systemic delivery of HLA-A*02:01, HLA-DRB1*04:01, human GM-CSF/IFN-α, and the human cytomegalovirus gB antigen.
    RESULTS: Human immune reconstitution was detectable in peripheral blood from 8 to 20 weeks after the transplantation of NSG-DKO. Human single positive CD4+ and CD8+ T-cells were detectable in lymphatic tissues (thymus, bone marrow, and spleen). LV delivery harnessed the detection of lymphocyte subsets in bone marrow (αβ and γδ T-cells and NK cells) and the expression of HLA-DR. Furthermore, RNA sequencing showed that LV delivery increased the expression of different human reactome pathways, such as defense responses to other organisms and viruses.
    CONCLUSIONS: Human T-cell development and reactivity are independent of the expression of murine MHCs in humanized mice. Therefore, humanized NSG-DKO is a promising new model for studying human immune responses, as it abrogates the xenograft mouse MHC interference.
    Keywords:  HLA; IFN; MHC; NSG; T-cell; humanized mice; immunization; lentivirus; stem cell transplantation
    DOI:  https://doi.org/10.3390/cells13201686
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